Langerhans Cell Histiocytosis (LCH) is a disease in which tissue destruction is caused by accumulation of histiocytes related to Langerhans cells (LC), the antigen presenting dendritic cells of skin. Although these pathologic LC's (PLC's) are clonal and overexpress p53, the high rate of remission in response to local treatment has led to the consensus that LCH is not a malignancy. LCH lesions can be localized and easily treated, or disseminated and lead to multiorgan failure and death. LC's are motile cells and their trafficking in vivo is tightly regulated. Normal resting LC's express the chemokine receptor CCR6 which directs them to mucocutaneous inflammatory sites where its ligand is secreted. Once LC's ingest antigen and become activated, they down- regulate CCR6 and up-regulate CCR7. This attracts LC's to lymph nodes, the source of CCR7's ligands, where they present antigen to T cells. Our preliminary data demonstrate that despite having characteristics of activated LC's, PLC's show persistent expression of CCR6 explaining, in part, their accumulation at inappropriate tissue sites. The experiments in this proposal are designed to elucidate the pathobiology and pathogenesis of LCH by testing the hypotheses that: (1) Dysregulated expression of chemokines and their receptors may be responsible for the persistence of PLC's in target organs; and (2) Clonal PLC's arise from LC's because of the expression of specific genes. To test these hypotheses, I propose the following specific aims: Specific Aim 1. Test primary LCH tissues for abnormalities in chemokine and chemokine receptor expression. This will be done using custom chip-based hybridization techniques and confirmed by immuno- histochemistry. Correlates will be made to a clinical database.